Identification and evaluation of biomarkers for Huntington’s disease

Abstract

Huntington’s disease (HD) is a devastating, incurable inherited neurodegenerative disorder that
commonly affects adults in mid-life. Despite encouraging results from in vitro and animal trials,
disease-modifying therapeutic trials in HD are limited by a lack of tools to track disease progression.
HD is clinically heterogeneous, and current clinical rating scales lack sensitivity and specificity,
particularly over relatively short time periods. Improvements in the precision of objective
measurement of disease progression in HD could lead to state markers (biomarkers) better able to
predict onset, detect progression and measure the effects of therapeutic intervention. Biomarkers
capable of detecting disease-related changes in premanifest gene carriers will be essential for
clinical trials of treatments to delay onset. Imaging, clinical and cognitive assessment as well as
laboratory markers have all been proposed as biomarkers, but few measures have been quantified
over short time intervals or shown to be predictive of clinical change over longer periods.
A robust panel of biomarkers from a number of modalities will be necessary to progress to
interventional clinical trials of disease-modifying therapies in HD, using biomarkers to measure the
success or failure of an intervention. Such cross-validation requires simultaneous multimodal
biomarker evaluation within a suitable cohort of subjects studied longitudinally.
This thesis describes a multi-modal approach to the discovery and evaluation of potential
biomarkers for Huntington's disease in a large cohort of human volunteers. After reviewing the
relevant features of Huntington's disease and current state of biomarker research in Huntington's
disease, several approaches to, and outcomes from, biomarker discovery and evaluation are
described, including proteomic profiling, targeted ELISA, multiplex inflammatory profiling and
measurement of whole-brain atrophy by longitudinal magnetic resonance imaging. The thesis draws
together these different approaches and summarises the contributions to both biomarker research
and our understanding of the neurobiology of HD that the work has generated.